Sivelestat sodium improves post-resuscitation brain outcomes possibly by inhibiting cell pyroptosis via inactivating...

Sivelestat sodium (SS) is shown to protect vital organs against regional ischemic stimuli. We investigated its effects on brain outcomes after global ischemic stimuli resulted from cardiac arrest (CA) and resuscitation. Adult pigs were randomly divided into sham (S), cardiopulmonary resuscitation (CPR), and CPR + SS groups. The animals were subjected to 9 mins of CA followed by 6 mins of CPR. After resuscitation, a dose of 10 mg/kg of SS was intravenously administered for 60 mins. Post-resuscitation brain injury and neurological function were regularly evaluated. Brain hippocampus tissues were harvested to measure histopathological injury, cell apoptosis, pyroptosis-related proteins and proinflammatory cytokines, and the cGAS/STING/TBK1 pathway. Consequently, post-resuscitation brain injury and neurological dysfunction were observed in those animals experiencing the CA/CPR procedure. However, they were significantly milder in the CPR + SS group than in the CPR group. Hippocampal histopathological injury and apoptosis were observed after resuscitation in the CPR and CPR + SS groups. Nevertheless, SS treatment significantly decreased both of them compared with the CPR group. Furthermore, pyroptosis-related proteins were upregulated, its-related proinflammatory cytokines were increased, and the cGAS/STING/TBK1 pathway was activated in post-resuscitation hippocampus in the CPR and CPR + SS groups. Likewise, SS treatment significantly reversed the changes of pyroptosis-related proteins and proinflammatory cytokines, and the cGAS/STING/TBK1 pathway compared to the CPR group. Thus, SS treatment was effective in improving post-resuscitation brain outcomes, and its protective role was possibly related to the inhibition of cell pyroptosis through the inactivation of the cGAS/STING/TBK1 pathway.